PROJECT SUMMARY/ABSTRACT Chemosensory signaling through the vagus nerve is an important component of the gut-brain axis, relaying information about the presence of nutrients and irritants within the lumen of the gut. Vagal sensory neurons transmit these signals from the gut to the brainstem, activating neural circuits to modulate the rate of digestion, or trigger emesis or diarrhea. Although the physiology of this circuit has been studied for decades, only recently have the molecular details of the receptors, cells, and signaling mechanisms begun to be defined. Pioneering work has identified two specific populations of vagal sensory neurons that play distinct roles for signaling stretch in the stomach and nutrients in the duodenum. This demonstrates that vagal neurons can encode sensory information in a labeled-line fashion, ie one line for stretch, one line for nutrients. Apart from these two specific vagal sensory populations innervating the gut, other populations of neurons responsible for irritant sensing, or nutrient sensing outside of the duodenum/proximal intestine remain undefined. Basic information about the repertoire of vagal sensory neurons innervating the gut and the types of information they encode are lacking. The goal of this proposal is to define the chemosensory circuits for detecting nutrients and irritants in the gut by addressing the following questions: 1) How is gut nutrient and irritant information encoded by vagal sensory neurons? 2) Can activity dependent labeling techniques be used for circuit mapping and molecular characterization of functional subsets of vagal sensory neurons?